chr17-76007414-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001988.4(EVPL):c.5791G>A(p.Val1931Met) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,603,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000072 ( 0 hom. )
Consequence
EVPL
NM_001988.4 missense
NM_001988.4 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 4.16
Genes affected
EVPL (HGNC:3503): (envoplakin) This gene encodes a member of the plakin family of proteins that forms a component of desmosomes and the epidermal cornified envelope. This gene is located in the tylosis oesophageal cancer locus on chromosome 17q25, and its deletion is associated with both familial and sporadic forms of oesophageal squamous cell carcinoma. Patients suffering from the autoimmune mucocutaneous disorder, paraneoplastic pemphigus, develop antibodies against the encoded protein. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04193011).
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EVPL | ENST00000301607.8 | c.5791G>A | p.Val1931Met | missense_variant | 22/22 | 1 | NM_001988.4 | ENSP00000301607.3 | ||
EVPL | ENST00000586740.1 | c.5857G>A | p.Val1953Met | missense_variant | 22/22 | 1 | ENSP00000465630.1 | |||
EVPL | ENST00000589231.1 | c.28G>A | p.Val10Met | missense_variant | 1/2 | 3 | ENSP00000467717.1 | |||
EVPL | ENST00000587569.5 | n.6260G>A | non_coding_transcript_exon_variant | 20/20 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000493 AC: 75AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000141 AC: 35AN: 247836Hom.: 0 AF XY: 0.000127 AC XY: 17AN XY: 133936
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GnomAD4 exome AF: 0.0000723 AC: 105AN: 1451642Hom.: 0 Cov.: 31 AF XY: 0.0000749 AC XY: 54AN XY: 720540
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GnomAD4 genome AF: 0.000492 AC: 75AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43AN XY: 74466
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2021 | The c.5791G>A (p.V1931M) alteration is located in exon 22 (coding exon 22) of the EVPL gene. This alteration results from a G to A substitution at nucleotide position 5791, causing the valine (V) at amino acid position 1931 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N;.
PrimateAI
Benign
T
PROVEAN
Benign
.;N;.
REVEL
Benign
Sift
Uncertain
.;D;.
Sift4G
Uncertain
D;D;D
Polyphen
0.52
.;P;.
Vest4
0.15, 0.20
MVP
MPC
0.25
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at